All literature and patent citations appearing in this specification are hereby incorporated herein by reference.
First transition series elements are essential to the replication and growth of all cells and viruses. They are essential co-enzymes required in a variety of metabolic processes. Iron and copper can catalyze free radical formation leading to oxidative damage to tissues. Consequently, alterations of the bioavailability and function of first transition series elements can affect cell systems, metabolic processes, and complex phenomena that are affected by such processes.
It is generally appreciated that most body odors arise from chemical byproducts of microbial growth. Thus, antimicrobial agents such as triclosan are commonly added to personal care products and cosmetics to inhibit development of body odors (such as underarm odor) through inhibition of microbial growth. See, Antiperspirants and Deodorants, 2d Ed., K. Laden, Ed., 1999, Marcel Dekker, Inc., New York, N.Y.
It is also generally appreciated that tooth decay, gingival inflammation and periodontal disease are initiated by microbial growth on surfaces in the oral cavity. Thus, antimicrobial agents such as triclosan have been incorporated into toothpastes to inhibit such processes. See, Oral Hygiene Products and Practice, 1988 Morton Prader, Ed., Marcel Dekker, Inc., New York, N.Y.
It is also generally appreciated that skin aging is, in part, a consequence of cumulative oxidative damage to the skin, particularly related to free radical generation consequent to exposure to solar ultraviolet radiation. In part, such free radical generation occurs through iron-catalyzed Fenton reactions. Thus, personal care/cosmetics preparations have been formulated containing reducing agents such as vitamin E and C to scavenge free radicals and other oxidizing species and it has been proposed that iron chelators be added to sunscreens to inhibit free radical generation. See, Sunscreens Development Evaluation and Regulatory Aspects, 1997, N. J. Lowe, N. A. Shaath, M. A. Pothak, Eds., Marcel Dekker, Inc., New York, N.Y.
It is also generally appreciated that first transition series elements act as coenzymes in a variety of enzymatic systems (metalloenzymes). Interference with access to the metal site by agents that chelate, or combine with, the metal at open coordination sites results in inhibition of the enzymatic activity of such enzymes. See, Inhibition of Matrix Metalloproteinases Therapeutic Applications, 1999 R. A. Greenwald, S. Zucker, L. M. Golub, Eds., New York Academy of Sciences ANYAA9878 1-761.
It is also generally appreciated that complex tissue processes may be affected by one or more processes in which first transition series elements play a role. For example, reperfusion injury may be related to hydroxyl free radicals arising from iron-catalyzed Fenton reactions (see, xe2x80x9cPrevention of Hydroxyl Radical Formation: A Critical Concept for Improving Cardioplegia. Protective Effects of Deferoxamine,xe2x80x9d P. Menasche, et al., Circulation, 1987, vol. 76 (Suppl. V), 180-185) and local release of matrix metalloproteinase enzymes (see, xe2x80x9cInhibition of Matrix Metalloproteinase-2 (MMP-2) Released During Reperfusion Following Ischemia Reduces Myocardial Stunning Injury,xe2x80x9d G. Sawicki, et al., Can J. Cardiol. Vol. 15, Suppl. D, 1999).
Published international patent application WO 97/01360 (xe2x80x9cCompounds With Chelation Affinity and Selectivity For First Transition Series Elements, and Their Use in Medical Therapy and Diagnosis,xe2x80x9d applicant: CONCAT, LTD., publication date Jan. 16, 1997, application number: PCT/US96/10785) discloses compositions and methods relating to a family of chelating agents having high affinity and specificity for first transition series elements. Claims include their use in inhibiting bacterial and fungal growth on a surface, including body surfaces, treating conditions dependent on bioavailability of first transition series elements in a patient, and treating conditions that are mediated by free radical or oxidation related tissue destruction.
The present specification demonstrates that the family of chelating agents disclosed in WO 97/01360 are capable of being used in cosmetics and personal care products to inhibit odor development (such as for example underarm odor), to inhibit replication of microorganisms associated with tooth decay and oral disease, and to inhibit oxidation and free radical damage to the skin. This specification also demonstrates that this family of chelating agents is capable of inhibiting enzymatic activity of metalloenzymes containing first transition series elements. Still further, this specification demonstrates that this family of chelating agents inhibits reperfusion injury, possibly as a consequence of their ability to inhibit generation of hydroxyl free radicals and/or inhibition of metalloenzymes such as the matrix metalloproteinases.
This invention resides in the discovery that a class of substituted polyaza compounds showing affinity and selectivity for first transition series elements (atomic numbers 21-30), by virtue of their ability to decrease the bioavailability and/or biochemical action of the first transition series elements, are useful in personal care products to decrease odor arising from microbial growth on body surfaces and in body cavities, decrease microbial growth on teeth, plaque, and gums that cause tooth decay and gum disease, inhibit oxidative damage to the skin, inhibit enzymatic action of metalloenzyme dependent on first transition series elements, and inhibit reperfusion injury. These effects are achieved by application or administration of the substituted polyaza compounds as either free ligands or as conjugated compounds, or as physiological salts of the free ligands or conjugated compounds.
Abbreviations
Abbreviations are used herein, in conformation with standard chemical practice, as follows: Bz, benzyl; Me, methyl; Et, ethyl Pr, propyl; iPr, isopropyl; iBu, isobutyl; Bu, butyl; tBu, isopropyl; tertiary-butyl; Ts, para-toluenesulfonyl; Tf, trifluoroacetate; DMSO, dimethylosulfoxide; DMF, dimethylformamide; DEK, diethyl ketone (3-pentanone); MeOH, methanol; LDA, lithium diisopropylamide; THF, tetrahydrofuran; Py, pyridine; Ac, acetyl; Ac2O, acetic anhydride.
Embodiments of the Invention
This invention provides methods useful in personal care products to decrease odor arising from microbial growth on body surfaces and in body cavities, to decrease microbial growth on teeth, plaque and gums that cause tooth decay and gum disease, to inhibit oxidative damage to the skin, to inhibit enzymatic action of metalloenzymes dependent on first transition series elements, and to inhibit reperfusion injury. The in vivo methods involve administering to a patient or host a chelating agent (or ligand) which is capable of complexing first transition series elements as well as elements with chemical characteristics similar to those of first transition series elements. For the diagnostic methods, the chelating agent is administered as a complex of radioisotopic or paramagnetic cations of first transition series elements (or those with similar properties).
Among the ligands used in the practice of the present invention are those represented by the following Formulas I through IV: 
In Formulas I through IV, R1, R2, R3, and R4 may be the same or different on any single molecule, and the same is true for R11, R12, and R13, for
R21, R22, and R23, and for R31, R32, and R33. Each of these symbols (R1 through R33) represents H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenoxy, alkenylthio, aryloxy, arylthio, alkyl interrupted by one or more oxa (xe2x80x94Oxe2x80x94), alkenyl interrupted by one or more oxa (xe2x80x94Oxe2x80x94), alkyl interrupted by one or more thia (xe2x80x94Sxe2x80x94), alkenyl interrupted by one or more thia (xe2x80x94Sxe2x80x94), aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, or hydroxyarylalkyl, provided only that these groups that do not interfere with complexation and that they are not combined in a manner that results in a chemically unstable configuration. The alkyl, alkenyl and aryl groups, or portions of groups, in the foregoing list can also be substituted with one or more halogen atoms.
In addition to the radicals and radical subclasses listed above, R1, R4, R11, R21 and R31 are further defined to include: 
In Formula V, R41, R42, and R43 may be the same or different on any single radical, and are defined as H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenoxy, alkenylthio, aryloxy, arylthio, alkyl interrupted by one or more oxa (xe2x80x94Oxe2x80x94), alkenyl interrupted by one or more oxa (xe2x80x94Oxe2x80x94), alkyl interrupted by one or more thia (xe2x80x94Sxe2x80x94), alkenyl interrupted by one or more thia (xe2x80x94Sxe2x80x94), aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, or hydroxyarylalkyl, provided only that these groups that do not interfere with complexation and that they are not combined in a manner that results in a chemically unstable configuration. Here again, the alkyl, alkenyl and aryl groups, or portions of groups, in the foregoing list can also be substituted with one or more halogen atoms. R44 in Formula V is defined as H, hydroxy, amino, alkyl, alkyl interrupted by oxa (xe2x80x94Oxe2x80x94), alkoxy, aryl, aryloxyalkyl, alkoxyaryl, or any of these groups in which the alkyl and aryl portions are substituted with one or more halogen atoms. Again, the groups are selected such that they do not interfere with complexation and are not combined in a manner that results in a chemically unstable configuration.
The index n is either zero or 1.
The symbol X represents any of the following groups: 
In these formulas, R41, R42, R43, and R44 may be the same or different on any single radical, and each has the same definition as that given above for R41, R42, and R43.
R46, R47, R48 and R49 may be the same or different on any single radical, and are each defined as H, or alkyl or aryl groups that do not interfere with complexation. R46 and R47 may further be combined as a single divalent group, thereby forming a ring structure. R48 and R49 are further defined to include alkoxy, alkyl interrupted by oxa (xe2x80x94Oxe2x80x94), aryloxyalkyl, and alkoxyaryl, combine in a manner that results in a chemically stable configuration. All alkyl and aryl groups in this paragraph, including alkyl and aryl portions of groups, are optionally substituted with one or more halogen atoms.
R50, R51, and R52 may be the same or different on any single radical, and are each defined as H, alkyl, alkenyl, aryl, arylalkyl, alkyloxy, alkylthio, alkenyloxy, alkenylthio, aryloxy, arylthio, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, or hydroxyarylalkyl.
The index m is an integer which is either 1, 2, or 3.
Returning to Formulas I through IV, further variations within the scope of this invention are as follows:
(1) Internal cyclizations within these formulas at the nitrogen atoms, formed by joining together any two of the R1 and R4 groups in Formula I, any two of the R11 groups in Formula II, any two of the R21 groups in Formula III, or any two of the R31 groups in Formula IV, as a single divalent group bridging the two nitrogen atoms, the single divalent group having the formula 
xe2x80x83in which R2 and R3 are as defined above, and s is at least 2, preferably 2 or 3;
(2) Dimers or other two-molecule combinations of Formulas I through IV (the molecules being the same or different), formed by bridging the molecules together through one or more divalent groups of Formula VI (as defined above) substituted for any one or two of the R11 groups in Formula II, any one or two of the R21 groups in Formula III, or any one or two of the R31 groups in Formula IV;
(3) Internal cyclizations at common carbon atoms within these formulas to form homocyclic rings, by joining one or more of the R2, R12, R22, or R32 groups to one or more of the R3, R13, R23, or R33 groups at the same carbon atom, as a single divalent group of Formula VI (as defined above), and forming one or more such homocyclic rings per structure in this manner; and
(4) Internal cyclizations involving two carbon atoms separated by a nitrogen atom within these formulas to form heterocyclic rings, by joining any two adjacent R2 groups in Formula I, any two adjacent R12 groups in Formula II, any two adjacent R22 groups in Formula III, or any two adjacent R32 groups in Formula IV, as a single divalent group of Formula VI (as defined above) and forming one or more such heterocyclic rings per structure in this manner.
In Formula I, the subscripts p and q may be the same or different, and are each either 2 or 3. The subscript r is 0 to 4, inclusive, with the proviso that in the absence of a ring structure r is 1 to 4, inclusive. Preferably, r is 1 or 2.
In Formula II, t, u, and v may be the same or different, and are each either 2 or 3. The value of w is at least 1, more preferably 1 to 4, inclusive, still more preferably 1 to 3, inclusive, and most preferably either 1 or 2.
The terms used in connection with these formulas have the same meaning here as they have in the chemical industry among those skilled in the art. The term xe2x80x9calkylxe2x80x9d thus encompasses both straight-chain and branched-chain groups and includes both linear and cyclic groups. The term xe2x80x9calkenylxe2x80x9d refers to unsaturated groups with one or more double bonds and includes both linear and cyclic groups. The term xe2x80x9carylxe2x80x9d refers to aromatic groups or one or more cycles.
For all such groups, those which are useful in the present invention are those that do not impair or interfere with the formation of the chelate complexes. Within this limitation, however, the groups may vary widely in size and configuration. Preferred alkyl groups are those having 1 to 8 carbon atoms, with 1 to 4 carbon atoms more preferred. Prime examples are methyl, ethyl, isopropyl, n-propyl, and tert-butyl. Preferred aryl groups are phenyl and naphthyl, particularly phenyl. Preferred arylalkyl groups are phenylethyl and benzyl, and of these, benzyl is the most preferred. Preferred cycloalkyl groups are those with 4 to 7 carbon atoms in the cycle, with cycles of 5 or 6 carbon atoms particularly preferred. Preferred halogen atoms are chlorine and fluorine, with fluorine particularly preferred.
One particularly preferred subclass of compounds within Formula I are those in which R1 is alkyl, alkenyl, aryl, arylalkyl, or cycloalkyl, substituted at the xcex2-position with hydroxy. Further preferred are compounds in which one or more, and preferably two or more, of such groups (R1, R11, R21 and R31) on the same formula are substituted at the xcex2-position with hydroxy. Still further preferred are compounds in which the xcex2-hydroxy substituted groups are further substituted at the xcex2-position with at least one hydroxymethyl, alkoxymethyl, alkenoxymethyl, aryloxymethyl, or combinations thereof, all of which may also be further substituted with halogen. Included among these are compounds of Formula III in which one or more of the R21 groups are substituted at the xcex2-position with hydroxy and also with hydroxymethyl, alkoxymethyl, alkenoxymethyl, or aryloxymethyl, all of which may also be further substituted with halogen, and the R22 and R23 groups are all hydrogen atoms.
Certain specific groups for R1, R11, R21, and R31 are particularly preferred. These are 2-hydroxy(2,2-diisopropoxymethyl)ethyl and (3-hydroxy-6,6,7,7-tetramethyl-1,5-dioxacyclohept-3-yl)methyl.
Where indicated, physiologically or pharmacologically compatible salts of the ligands, or complexes thereof, which have an excess of acidic groups are formed by neutralizing the acidic moieties of the ligand with physiologically or pharmacologically compatible cations from corresponding inorganic and organic bases and amino acids. Examples are alkali and alkaline earth metal cations, notably sodium. Further examples are primary, secondary and tertiary amines, notably, ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine, and N-methylglucamine (commonly referred to as xe2x80x9cmegluminexe2x80x9d). Examples of amino acid cations are lysines, arginines and ornithines.
Similarly, physiologically and pharmacologically compatible salts of those ligands which have an excess of basic groups are formed by neutralizing the basic moieties of the ligand with physiologically or pharmacologically compatible anions from corresponding inorganic and organic acids. Examples are halide anions, notably chloride. Further examples are sulfates, bicarbonate, acetate, pyruvate and other inorganic and organic acids.
Pharmaceutical compositions comprising the chelates described herein are prepared and administered according to standard techniques. The pharmaceutical compositions can be administered parenterally, i.e., intraarticularly, intravenously, subcutaneously, or intramuscularly. Suitable formulations for use in the present invention are found in Remington""s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed. (1985).
The chelate compositions can be administered intravenously. Thus, this invention provides compositions for intravenous administration which comprise a solution of the chelate suspended in an acceptable carrier, preferably an aqueous carrier. A variety of aqueous carriers may be used, e.g., water, buffered water, 0.9% isotonic saline, and the like. These compositions may be sterilized by conventional, well known sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.
The concentration of chelates, in the pharmaceutical formulations can vary widely, i.e., from less than about 0.05%, usually at or at least about 2-5% to as much as 10 to 30% by weight and will be selected primarily by fluid volumes, viscosities, etc., in accordance with the particular mode of administration selected. For diagnosis, the amount of chelates in administered complexes will depend upon the particular metal cation being used and the judgement of the clinician. For use in magnetic resonance imaging the dose typically is between 0.05 to 0.5 millimoles/kg body weight.
In general, any conventional method for visualizing diagnostic imaging can be used, depending upon the label used. Usually gamma and positron emitting radioisotopes are used for imaging in nuclear medicine and paramagnetic metal cations are used in magnetic resonance imaging.
The methods of the present invention may be practiced in a variety of hosts. Preferred hosts include mammalian species, such as humans, non-human primates, dogs, cats, cattle, horses, sheep, and the like.